Project Summary/Abstract Non-small cell lung cancers harboring fusions in the anaplastic lymphoma kinase (ALK) gene make up approximately 4% of non-small cell lung cancers (NSCLC), thus representing thousands of the ~200,000 lung cancers annually diagnosed in the United States. Patients with ALK-positive lung cancers can have dramatic and durable responses to ALK-targeted tyrosine kinase inhibitors (TKIs), however acquired drug resistance is inevitable after a median of 1-2 years. Several potent next generation ALK TKIs (e.g. ceritinib, alectinib, brigatinib) are now FDA approved and are improving treatment outcomes in ALK-positive NSCLC. However, the rarity of ALK-positive NSCLC has limited our ability to understand and develop management strategies for ALK TKI resistance. The SPACEWALK study leverages genomic analysis of plasma cell-free DNA (cfDNA) to study ALK TKI resistance remotely from NSCLC patients developing resistance to next-generation ALK TKIs. Our center has used remote consent and specimen collection extensively over recent years to study rare lung cancer genotypes. We also have led the development and validation of assays for genotyping of plasma cfDNA. In this study we combine these approaches to study a rare lung cancer population where precision treatment of has the potential to improve patient outcomes. Eligible patients are screened remotely and consent via a web- based system. Blood is collected and submitted for plasma next-generation sequencing (NGS) at a clinical laboratory. Results are returned within 1-2 weeks to the patient and their oncologist and describe the potential clinical implications of any resistance mutations detected. The patient is then followed to study the clinical outcome on subsequent treatments received. A follow-up plasma specimen is collected 2-3 weeks after starting therapy to evaluate response in plasma cfDNA. Our overarching hypothesis is that such a remote participation study using plasma NGS will enrich our understanding of resistance mutations in ALK-positive lung cancer, while also assessing value of plasma NGS in predicting benefit from different ALK TKIs. Moreover, this novel methodology has the potential to be applied widely across a range of cancer genotypes, dramatically impacting our ability to study (and thus develop treatments for) cancer patients with targeted therapy resistance.